Major factor determining corticosteroid receptor binding and pharmacodynamics are being measured and improved mathematical models for quantitating the pharmacokinetics and pharmacodynamics (PK/PD) of corticosteroids are being sought. This has resulted in evolution of our "fifth generation" model for receptor-mediated pharmacogenomics of methyprednisolone (MPL) and utilization of structure-activity principles to show partial generalization to other corticosteroids. Our original fourth specific aim was to use quantitative gene array techniques to compare types and time patterns of altered expression of diverse genes by corticosteroids. An extensive microarray study shows that there may be a limited array of genomic response patterns produced by MPL this yielding a hypothesis that while steroids have myriad physiologic and pharmacologic effects (perhaps hundreds) the underlying 'rules of biology' governing gene expression for these complex biological systems may be limited to a few mechanisms that may be better identified and quantitated with mathematical models. A formidable bioinformatics, data analysis, biochemical pathway, and modeling assessment task remains in order to resolve the meaning and relevance of current and prospective data arrays. We will seek an improved series of PK/PD models for diverse genomic effects of corticosteroids based on; conducting an extensive literature search of pathways and regulation of gene expression with design of an accessible filing system, constructing metabolic and regulatory pathway analysis for each affected gene with focus on kinetics and mechanisms, evolve more comprehensive mechanism-based PK/PD genomic models utilizing this information based and expand our data base with new and instructive pharmacologic gene array studies. This requires enlarging our research team of mathematical modelers and molecular biologists to include experts in bioinformatics and biochemical pathway analysis. These studies will improve the pharmacologic rationale of corticosteroid therapy as well as continue developing more generalized pharmacogenomic models which apply to drugs causing responses by complex and indirect mechanisms. [unreadable] [unreadable]